Project Summary There is currently no disease modifying treatment available for Alzheimer?s disease (AD) and our poor understanding of the factors that contribute to its development stands as a significant barrier to identifying effective preventative measures or treatments for this disease. This proposal seeks to advance our understanding of AD etiology by testing the hypothesis that infection with viruses that express inhibitors of protein phosphatase 2A (PP2A) can contribute to its development. Specifically, we will test a model wherein infection by PP2A inhibiting viruses could contribute to AD by triggering tau pathology that then propagates from infected cells to adjacent cells and brain regions in a pattern consistent with AD progression. This hypothesis is supported by three well-established lines of evidence from studies conducted in humans and animal models including: evidence demonstrating a role for PP2A in AD and tau pathology, the observation that tau pathology propagates to adjacent cells, and the fact that multiple human viruses express PP2A inhibiting proteins as a common strategy for coopting the physiology of their host cells. In this proposal, we will screen human brain tissue using a novel, state of the art method (ViroCap) and laser capture microdissection to identify and to test for associations between sites of viral infection and tau histopathology. This work will advance our understanding of the factors that contribute to the development of AD, with potential clinical applications including the development of tests to identify individuals at increased risk for AD as a result of infection with PP2A inhibiting viruses, the development of vaccines or antiviral therapies to prevent increased AD risk resulting from infection with these viruses, or the development of pharmacological interventions that reduce AD risk in infected individuals by increasing PP2A activity. In this proposal, we will also create an animal model of the seeding of tau pathology by viral PP2A inhibitors for use in understanding the mechanisms underlying their effects and identifying potential therapeutic approaches to combat them.